Charcot–Marie–Tooth type 1A (CMT1A) neuropathies linked to the misexpression of peripheral myelin protein 22 (PMP22) are progressive demyelinating disorders of the peripheral nervous system. In this study we asked whether dietary restriction by intermittent fasting (IF) could alleviate the neuropathic phenotype in the Trembler J (TrJ) mouse model of CMT1A. Our results show that neuropathic mice kept on a five month long IF regimen had improved locomotor performance compared to ad libitum (AL) fed littermates. The functional benefits of this dietary intervention are associated with an increased expression of myelin proteins combined with a thicker myelin sheath, less redundant basal lamina, and a reduction in aberrant Schwann cell proliferation. These morphological improvements are accompanied by a decrease in PMP22 protein aggregates, and enhanced expression of cytosolic chaperones and constituents of the autophagy–lysosomal pathway. These results indicate that dietary restriction is beneficial for peripheral nerve function in TrJ neuropathic mice, as it promotes the maintenance of locomotor performance.
"Similar to what has been observed in other protein misfolding disorders (Morimoto , 2011), the levels of HSP70 are elevated in the nerves of C22 mice, as compared with the age-matched Wt. A protective role for chaperones in neuropathies is supported by studies where exogenous induction of the heat-shock response either by diet restriction or pharmacologic modulation prevents the aggregation of PMP22 while promoting the myelination capacity of the Schwann cells (Rangaraju et al., 2008, 2009; Madorsky et al., 2009). In light of these results, why are the chaperones unable to prevent protein aggregation in neuropathic Schwann cells? "
[Show abstract][Hide abstract] ABSTRACT: Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary demyelinating neuropathy linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Transgenic C22 mice, a model of CMT1A, display many features of the human disease, including slowed nerve conduction velocity and demyelination of peripheral nerves. How overproduction of PMP22 leads to compromised myelin and axon pathology is not fully understood, but likely involves subcellular alterations in protein homeostatic mechanisms within affected Schwann cells. The subcellular response to abnormally localized PMP22 includes the recruitment of the ubiquitin-proteasome system (UPS), autophagosomes and heat shock proteins. Here we assessed biochemical markers of these protein homeostatic pathways in nerves from PMP22-overexpressing neuropathic mice between the ages of 2-12 months to ascertain their potential contribution to disease progression. In nerves of 3 week old mice, using endoglycosidases and western blotting, we found altered processing of the exogenous human PMP22, an abnormality that becomes more prevalent with age. Along with the ongoing accrual of misfolded PMP22, the activity of the proteasome becomes compromised and proteins required for autophagy induction and lysosome biogenesis are upregulated. Moreover, cytosolic chaperones are consistently elevated in nerves from neuropathic mice, with the most prominent change in HSP70. The gradual alterations in protein homeostatic response are accompanied by Schwann cell de-differentiation and macrophage infiltration. Together, these results show that while subcellular protein quality control mechanisms respond appropriately to the presence of the overproduced PMP22, with aging they are unable to prevent the accrual of misfolded proteins.
"As ambulation is frequently impaired in patients affected by CMT1A and other types of hereditary neuropathies, this observation, if confirmed in further studies, suggests that a low calorie diet may be indicated in CMT1A. Interestingly, intermittent fasting prevents the development of neuropathy in an animal model of CMT1A . As expected, the presence of DM reduces the amplitude of ulnar nerve in CMT1A patients without influencing MNCV. "
[Show abstract][Hide abstract] ABSTRACT: Charcot-Marie-Tooth type 1A (CMT1A) is the most common inherited neuropathy. The phenotype of patients affected by CMT1A is highly variable and may be influenced by several conditions. We evaluated how comorbidities such as diabetes, hypothyroidism, exposure to toxins and obesity can modify or exacerbate the clinical and neurophysiological phenotype of CMT1A patients. Disability was measured using the classic CMT neuropathy score. Compared to controls, all groups of CMT1A patients with comorbidities had higher CMT neuropathy score. In particular, patients with CMT1A and diabetes mellitus show motor subscores which are significantly higher than in control CMT1A. Amplitudes of ulnar CMAP are lower in patients with CMT1A and diabetes mellitus, but not at a significant level. As expected, motor nerve conduction velocity is not influenced by any of the comorbidities. The presence of concomitant diseases shows a tendency to worsen the clinical and neurophysiological CMT1A phenotype, especially in patients with CMT1A and diabetes mellitus, where higher values in the CMT neuropathy score and clinical motor subscore have been observed.
"While our studies have focused on examining the effects of these dietary interventions on protein homeostatic pathways, we found additional, overlapping mechanisms between the two approaches. Similar to the CR intervention in aged rats (Opalach et al., 2010), the IF regimen in neuropathic mice also muted the nerve inflammatory response and supported the maintenance of the myelinated Schwann cell phenotype (Madorsky et al., 2009). One could ask why it took five months of IF to see a significant improvement in the motor performance of neuropathic mice. "
[Show abstract][Hide abstract] ABSTRACT: The peripheral nervous system (PNS) comprises of an extensive network of connections that convey information between the central nervous system (CNS) and peripheral organs. Long myelinated nerve fibers are particularly susceptible to age-related changes, as maintenance of the insulating glial membrane requires extensive synthesis and processing of many proteins. In rodent models, peripheral demyelination caused by genetic risk factors or by normal aging are attenuated by intermittent fasting (IF) or calorie restriction (CR) supporting a role for dietary intervention in preserving neural function. This review will summarize recent studies examining mechanisms by which life-long CR or extended IF supports peripheral nerve health.
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